It is known that there exists a metabolic pathway called a 5-lipoxygenase pathway in the cascade of arachidonic acid and that arachidonic acid is converted to 5-hydroperoxyeicosatetraenoic acid (hereinafter may be referred to as 5-HPETE) by the function of 5-lipoxygenase ("Prostaglandin and Morbid States", edited by Seiitsu Murota, Tokyo Kagaku Dojin, 1984).
It is known that various leukotrienes can be synthesized by using this compound as an intermediate ("prostaglandin and Mobid States", edited by Seiitsu Murota, Tokyo Kagaku Dojin, 1984), and it is also known that, for example, leukotriene B4 of these leukotrienes has a strong activity of leukocyte migration and is a mediator for inflammation, and that leukotriene C4 and D4 are mediators for asthma ("Prostaglandin and Morbid States", edited by Seiitsu Murota, Tokyo Kagaku Dojin, 1984).
Hence, searches for medicines having an inhibitory effect on 5-lipoxygenase have been performed extensively from the view point that it may be anticipated to prevent and treat various diseases caused by the excess production of leukotrienes (e.g., allergic diseases, bronchial asthma, edema, various inflammatory diseases) by using medicines capable of inhibiting 5-lipoxygenase effectively, which is an incipient enzyme of a biosynthesis system of these leukotrienes.
On the other hand, there exists a metabolic pathway called a 12-lipoxygenase pathway in the cascade of arachidonic acid. 12-lipoxygenase is an enzyme present in platelets in a large amount and reacts with arachidonic acid to form 12-hydroperoxyeicosatetraenoic acid (hereinafter may be referred to as 12-HPETE), which is reduced to 12-hydroxyeicosatetraenoic acid (hereinafter may be referred to as 12-HETE).
The physiological meaning of metabolic products in the 12-lipoxygenase pathway has not been clear compared with that of the 5-lipoxygenase pathway, but recently various physiological activities of the metabolic products have become clear mainly on 12-HPETE and 12-HETE of its main metabolic products.
Physiological activities thereof may be exemplified as below. Namely, a possibility is pointed out that 12-lipoxygenase metabolic products may be concerned with arteriosclerosis by controling the function of the aggregation and adhesion of platelets and by enhancing the migration of vascular smooth muscle cells ("Gendai Iryo", Vol. 21, No. 11, pp. 3109-3113, 1989), and another possibility is also suggested that 12-HPETE may be an initiator for the occurrence of vasospasm after subarachnoid hemorrhage ("Gendai Iryo", Vol. 21, No. 11, pp. 3127-3130, 1989), and further it is shown that 12-HETE enhances the adhesion and metastasis of some kinds of cancer cells to vascular endothelial cells ("Gendai Iryo", Vol. 22, special issue, pp. 56-57, 1990). According to the above facts, it is anticipated that substances inhibiting 12-lipoxygenase may be used as medicines for preventing and treating various circulatory diseases such as arteriosclerosis and vasospasm and for preventing of the metastasis of some kinds of cancers effectively.
As a substance having a 12-lipoxygenase inhibitory effect is known baicalein, a kind of native flavonoid ("Biochemical and Biophysical Research Communications", Vol. 105, No. 3, pp. 1090-1095, 1982). In addition, a hydroxamic acid derivative (official gazette of Japanese Patent Kokai Publication No. 216961/1989, official gazette of Japanese Patent Kokai Publication No. 752/1990 and official gazette of Japanese Patent Kokai Publication No. 196767/1990) and a caffeic acid derivative (official gazette of Japanese Patent Kokai Publication No. 275552/1989 and official gazette of Japanese Patent Kokai Publication No. 235852/1990) are known.
On the other hand, coumarin derivatives are generally synthesized chemically or isolated from natural sources and purified, and as a prior art referred to a lipoxygenase inhibitory activity is known, for example, the following matter of 1):
1) Information about esculetin (6,7-dihydroxycoumarin) ("Biochimica et Biophysica Acta", Vol. 753, No. 1, pp. 130-132, 1983) is known, and it is reported that the compound showed IC.sub.50 values of 4.times.10.sup.- 6M and 2.5.times.10.sup.-6 M to the 5-lipoxygenase and 12-lipoxygenase of mastocytoma cells respectively. PA0 2) 6,7-dihydroxy-3-phenylcoumarin [(1) "Journal of the Chemical Society. C. Organic Chemistry", Vol. 16, pp. 2069-2070, 1969, and (2) "Zhurnal Prikladnoi Spektroskopii", Vol. 8, No. 6, pp. 1063-1066, 1968]. PA0 3) 7,8-dihydroxy-3-phenylcoumarin [(1) "Current Science", Vol. 35, No. 22, pp. 557-559, 1966, (2) "Zhurnal Prikladnoi Spektroskopii", Vol. 8, No. 6, pp. 1063-1066, 1968, (3) "Proceedings of the Indian Academy of Sciences, Section A", Vol. 56, pp. 71-85, 1962, (4) "Proceedings of the Indian Academy of Sciences, Section A", Vol. 59, No. 3, pp. 185-189, 1964, and (5) "Journal of Organic Chemistry", Vol. 19, pp. 1548-1552, 1954). PA0 4) 6,7-dihydroxy-3-(furan-2-yl)coumarin, and 7,8-dihydroxy-3-(furan-2-yl)coumarin ["Zhurnal Prikladnoi Spektroskopii", Vol. 8, No. 6, pp. 1063-1066, 1968]. PA0 5) 6,7-dihydroxy-3-(3-nitrophenyl)coumarin ("Journal of the Chemical Society. C. Organic Chemistry", Vol. 16, pp. 2069-1070, 1969). PA0 6) 7,8-dihydroxy-4-methyl-3-(4-nitrophenyl)coumarin ("Annales de la Societe Scientifique de Bruxelles. Series 1", Vol. 84, No. 3, pp. 383-388, 1971). PA0 7) 6,7-dihydroxy-4-methyl-3-phenylcoumarin [(1) "Farmaco, II (Pavia), Edizione Scientifica", Vol. 12, pp. 691-694, 1957, and (2) "Atti della accademia nazionale dei Lincei. Rendiconti, Classe di scienze fisiche, matematiche e naturali", Vol. 10, pp. 230-235, 1951]. PA0 8) 6,7-dihydroxy-3,4-diphenylcoumarin [(1) Pubblicazioni del centro di studio per la citogenetica vegetale del consiglio nazionale delle ricerche", Vol. 182, pp. 350-387, 1955, and (2) "Atti della accademia nazionale dei Lincei. Rendiconti, Classe di scienze fisiche, matematiche e naturali", Vol. 10, pp. 645-649, 1954]. PA0 9) 6,7-dihydroxy-3-(pyridin-3-yl)coumarin ("Journal of the Chemical Society. C. Organic Chemistry", Vol. 16, pp. 2069-2070, 1969). PA0 10) 7,8-dihydroxy-4-phenylcoumarin (Specification of U.S. Pat. No. 2,809,201). PA0 11) Baicalein (5,6,7-trihydroxyflavone) ("Biochemical and Biophysical Research Communications", Vol. 105, No. 3, pp. 1090-1095, 1982). PA0 12) 4',6,7-trihydroxyisoflavan ("Prostaglandins", Vol.28, No. 6, pp. 783-804, 1984). PA0 13) 4',7,8-trihydroxyisoflavan, and 6,7-dihydroxy-3',4'-dimethoxyisoflavan ("International Journal of Tissue Reactions", Vol. 11, No. 3, pp. 107-112, 1989).
As will be described later, however, the IC.sub.50 values shown by the compound are considerably large compared with those of the compounds of the present invention, and it is hard to say that it has a selectivity toward 12-lipoxygenase. In fact, comparative tests performed by the present inventors revealed that esculetin had considerably weaker inhibitory effect on 12-lipoxygenase than the compounds of the present invention and that esculetin showed inhibition activity also on 5-lipoxygenase to a similar extent, so that no selectivity was found.
Besides, as coumarin derivatives similar to the compounds of the present invention are known the following compounds 2)-10).
It has never been known, however, that these compounds have not only 12-lipoxygenase inhibitory activities but also 5-lipoxygenase inhibitory activities.
Furthermore, as those which are not coumarin derivatives but relatively similar to the compounds of the present invention and which referred to 12-lipoxygenase inhibitory activities or 5-lipoxygenase inhibitory activities are known the following compounds 11)-13) including the above-mentioned baicalein:
Of the above, the compound of 12) inhibited the formation of 5-lipoxygenase metabolic products in human peripheral leukocytes at a concentration of 10 uM completely but inhibited only 25% of the formation of 12-lipoxygenase metabolic products in platelets at the same concentration; hence the compound is known to be selective toward 5-lipoxygenase ("Prostaglandins", Vol. 28, No. 6, pp. 783-804, 1984). Besides, it is reported with regard to the compound of 13) that while the 5-lipoxygenase inhibitory activity of the compound in human peritoneal macrophages is 1-2 .mu.M based on an IC.sub.50 value, the 12-lipoxygenase inhibitory activity of the compound is 16-20 .mu.M based on the IC.sub.50 value ("International Journal of Tissue Reactions", Vol. 11, No. 3, pp. 107-112, 1989).
The compounds of the present invention have a remarkably strong 12-lipoxygenase inhibitory activity, being of the order of 10.sup.-9 to 10.sup.-8 M based on the IC.sub.50 values as will be described later. On the other hand, the IC.sub.50 values to 5-lipoxygenase are more than 10-60 times as large as those to 12-lipoxygenase, and hence they have a selective inhibitory activity against 12-lipoxygenase.
It could never been guessed from conventional information that the compounds of the present invention have such a activity.